In the last few years functional magnetic resonance imaging (fMRI) has become a powerful and widely used tool for investigating the working human brain. The small changes in the MR signal due to the Blood Oxygenation Dependent (BOLD) effect that accompany local changes in brain metabolism can be used to map patterns of brain activation during performance of a variety of sensory, motor and cognitive tasks. But despite the widespread use of fMRI techniques, the basic physiological and biophysical mechanisms underlying the observed signal changes are still poorly understood. The broad goal of the proposed work is to answer two basic questions: 1) What are the physiological changes accompanying human brain activation?, and 2) How can we quantitatively interpret observed MR effects in terms of physiological changes? This project brings together two lines of research that have developed in our laboratory over the last few years: 1) Theoretical mathematical modeling of the physiological changes occurring during activation and the quantitative translation of these changes into MR signal changes; and 2) Development and evaluation of MRI experimental techniques for quantitative perfusion measurements. Based on the theoretical modeling, we have framed this project around two central hypotheses: 1) The changes in cerebral oxygen metabolism (CMRO2) and cerebral blood flow (CBF) are tightly coupled during brain activation, but in a nonlinear fashion requiring large changes in CBF to support small changes in CMRO2 because of limited O2 extraction from the capillary; and 2) The temporal profile of signal changes observed in fMRI experiments is highly sensitive to the relative time courses for blood flow and blood volume changes during activation. These hypotheses will be tested using recently developed MRI techniques for measurement of perfusion and blood volume changes in combination with the conventional fMRI signal sensitive to blood oxygenation. Experiments will measure changes in these physiological variables during performance of four types of stimulation (sensorimotor, visual, auditory, and cognitive). The three sets of experiments to be performed are: 1) variable stimulus amplitude to vary the physiological response; 2. high temporal resolution measurements of the time course of BOLD signal, blood flow and blood volume changes; and 3) sustained activation to test the continued coupling of CBF and CMRO2. In addition, the theoretical models will be further developed to include viscoelastic properties of blood vessels. The end result of this work will be an experimental and theoretical characterization of the physiological changes accompanying human brain activation.